Case report
Laminopathies: A Pandora's box of heart failure, bradyarrhythmias and sudden death
Laminopatias: uma caixa de Pandora com insuficiência cardíaca, bradiarritmias e morte súbita
Hospital Distrital de Santarém, Santarém, Portugal
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The shape of pannus growth on the ventricular surface of the prosthesis removed from the prosthesis can be clearly seen. The concentric stenosis of the valve orifice area (black arrow) and the thrombosis on the atrial side causing valve blockage (white arrow) are evident. The mural blood clot removed from the left atrial appendage is shown.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "María Elena Arnáiz-García, Jose María González-Santos, María E. Bueno-Codoñer, Javier López-Rodríguez, María José Dalmau-Sorlí, Adolfo Arévalo-Abascal, Antonio Arribas-Jiménez, Alejandro Diego-Nieto, Javier Rodríguez-Collado, Jose María Rodríguez-López" "autores" => array:10 [ 0 => array:2 [ "nombre" => "María Elena" "apellidos" => "Arnáiz-García" ] 1 => array:2 [ "nombre" => "Jose María" "apellidos" => "González-Santos" ] 2 => array:2 [ "nombre" => "María E." "apellidos" => "Bueno-Codoñer" ] 3 => array:2 [ "nombre" => "Javier" "apellidos" => "López-Rodríguez" ] 4 => array:2 [ "nombre" => "María José" "apellidos" => "Dalmau-Sorlí" ] 5 => array:2 [ "nombre" => "Adolfo" "apellidos" => "Arévalo-Abascal" ] 6 => array:2 [ "nombre" => "Antonio" "apellidos" => "Arribas-Jiménez" ] 7 => array:2 [ "nombre" => "Alejandro" "apellidos" => "Diego-Nieto" ] 8 => array:2 [ "nombre" => "Javier" "apellidos" => "Rodríguez-Collado" ] 9 => array:2 [ "nombre" => "Jose María" "apellidos" => "Rodríguez-López" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0870255115000104" "doi" => "10.1016/j.repc.2014.08.024" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255115000104?idApp=UINPBA00004E" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204915000367?idApp=UINPBA00004E" "url" => "/21742049/0000003400000002/v2_201502270337/S2174204915000367/v2_201502270337/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2174204915000355" "issn" => "21742049" "doi" => "10.1016/j.repce.2014.08.022" "estado" => "S300" "fechaPublicacion" => "2015-02-01" "aid" => "589" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "simple-article" "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "crp" "cita" => "Rev Port Cardiol. 2015;34:137.e1-4" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 3636 "formatos" => array:3 [ "EPUB" => 227 "HTML" => 2876 "PDF" => 533 ] ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case report</span>" "titulo" => "Prosthetic aortic valve: A bone in the system" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "137.e1" "paginaFinal" => "137.e4" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Prótese valvular aórtica: «um osso na engrenagem»" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 862 "Ancho" => 2501 "Tamanyo" => 254845 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Transesophageal echocardiogram in mid-esophageal short- (A) and long-axis (B) views of the aortic prosthesis, showing two abscesses (A, asterisk) surrounding the single-disc mechanical prosthetic valve (A, cross). There appears to be no rupture from these abscesses (B, white arrow) to the left ventricular outflow tract.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Vitor Hugo Pereira, Joana Guardado, Marina Fernandes, Mário Lourenço, Inocência Machado, Isabel Quelhas, Olga Azevedo, António Lourenço" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Vitor Hugo" "apellidos" => "Pereira" ] 1 => array:2 [ "nombre" => "Joana" "apellidos" => "Guardado" ] 2 => array:2 [ "nombre" => "Marina" "apellidos" => "Fernandes" ] 3 => array:2 [ "nombre" => "Mário" "apellidos" => "Lourenço" ] 4 => array:2 [ "nombre" => "Inocência" "apellidos" => "Machado" ] 5 => array:2 [ "nombre" => "Isabel" "apellidos" => "Quelhas" ] 6 => array:2 [ "nombre" => "Olga" "apellidos" => "Azevedo" ] 7 => array:2 [ "nombre" => "António" "apellidos" => "Lourenço" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S0870255115000098" "doi" => "10.1016/j.repc.2014.08.023" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255115000098?idApp=UINPBA00004E" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204915000355?idApp=UINPBA00004E" "url" => "/21742049/0000003400000002/v2_201502270337/S2174204915000355/v2_201502270337/en/main.assets" ] "en" => array:19 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Case report</span>" "titulo" => "Laminopathies: A Pandora's box of heart failure, bradyarrhythmias and sudden death" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "139.e1" "paginaFinal" => "139.e5" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Nuno Cabanelas, Vítor Paulo Martins" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Nuno" "apellidos" => "Cabanelas" "email" => array:1 [ 0 => "ncabanelas@gmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Vítor Paulo" "apellidos" => "Martins" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Hospital Distrital de Santarém, Santarém, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Laminopatias: uma caixa de Pandora com insuficiência cardíaca, bradiarritmias e morte súbita" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The proteins lamin A and C polymerize to form the nuclear lamina, a meshwork of filaments on the nucleoplasmic side of the nuclear envelope, which separates the internal nuclear membrane from chromatin<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a> and is found in all differentiated cells of the organism. This mesh has a structural function, maintaining the shape and size of the nucleus. Nuclear lamins also play a role in gene regulation, DNA replication, RNA splicing, anchoring of other nucleoplasmic proteins, function and position of nuclear pores and heterochromatin organization.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">LMNA</span>, the gene encoding lamin A/C, is located on chromosome 1 (locus 1q21.2-21.3).<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a> In 1999, an <span class="elsevierStyleItalic">LMNA</span> mutation was shown to cause autosomal dominant Emery-Dreifuss muscular dystrophy.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Since then, over 450 mutations in this gene have been described and are implicated in a range of other diseases, which differ in their phenotypic expression and affect various organ systems including muscles, fatty tissue and peripheral nerves, as well as systemic involvement in the case of progerias. These entities are termed laminopathies, as shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Many mutations linked to laminopathies also affect the heart, in the form of dilated cardiomyopathy (DCM), with or without involvement of other striated muscle, conduction disturbances and propensity for sudden death.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The mechanism through which lamin A/C deficiency causes these phenotypes is not fully understood. Two hypotheses have been proposed: one in which cell death is caused by loss of structural integrity at the nuclear level; and the other in which gene expression explains the phenotypic alterations through abnormal interaction with transcription factors in protein synthesis.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">2,6</span></a> The disease is expressed histologically by fibro-adipose degeneration and atrophy of the affected tissues. At the level of cell ultrastructure, there may be partial membrane rupture, disorganization of the nuclear membrane pores and vacuolization.<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">7,8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">From the standpoint of practical cardiological management, these diseases can be considered as a single entity – cardiomyopathy associated with <span class="elsevierStyleItalic">LMNA</span> mutations, with or without different types of muscle involvement.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The development and accessibility of genetic study has led to more frequent identification of <span class="elsevierStyleItalic">LMNA</span> mutations in patients who would previously have been diagnosed as having idiopathic DCM. One caveat is that, as has occurred in early studies of other diseases, the initial series reported and associated prognosis may have been biased by the natural tendency to identify only cases with a more marked phenotypic expression.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Case report</span><p id="par0040" class="elsevierStylePara elsevierViewall">A 46-year-old man, a professional soccer player until the age of 34 and currently employed by a trucking company, was referred for cardiological assessment following detection of alterations on a routine ECG.</p><p id="par0045" class="elsevierStylePara elsevierViewall">He denied having suffered chest pain, palpitations, syncope, fainting episodes, exertional or nocturnal dyspnea, or any muscular problems. There was no relevant personal medical history.</p><p id="par0050" class="elsevierStylePara elsevierViewall">His family history included the death of a brother two years previously at age 60 following a fall from a motorcycle. According to his family, the autopsy report, to which we did not have access, revealed that trauma was not the cause of death but gave no further details.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Physical examination showed bradycardia (50 bpm) and deviation of the apical pulse to the left. No dysmorphism or muscle or joint malformations were observed and there were no changes on neurological examination.</p><p id="par0060" class="elsevierStylePara elsevierViewall">The baseline ECG showed sinus bradycardia, first-degree atrioventricular block (AVB), with PQ interval of 240 ms, poor R-wave progression in the precordial leads and deep S waves (41 mV in V2). The resting echocardiogram revealed left ventricular dilatation with no wall thickening, mildly depressed ejection fraction (45%) and mild diffuse hypokinesia. The ultrasound findings were confirmed by cardiac magnetic resonance imaging, which also excluded areas of late enhancement, fatty infiltration and edema.</p><p id="par0065" class="elsevierStylePara elsevierViewall">The patient underwent treadmill exercise echocardiography to investigate repolarization abnormalities suggestive of ischemia, arrhythmia and overall contractility. He achieved 14 min 48 s with the Bruce protocol. Increasingly frequent polymorphic ventricular extrasystoles were observed, with wide QRS complexes, and at peak exercise, pairs with the R wave close to the T peak. Ventricular contractility at peak exercise was strong, with almost complete systolic obliteration of the left ventricular cavity.</p><p id="par0070" class="elsevierStylePara elsevierViewall">On 24-hour Holter monitoring, ventricular tachycardia (VT) with five bizarre polymorphic complexes were documented, together with a period of idioventricular rhythm at 70 bpm.</p><p id="par0075" class="elsevierStylePara elsevierViewall">In the light of the findings of mild systolic dysfunction, first-degree AVB and sinus bradycardia, arrhythmic response to exercise and a short run of polymorphic VT, the patient was referred for genetic testing for <span class="elsevierStyleItalic">LMNA</span> mutations. The mutation c.1039G>A was found in heterozygosity in exon 6 of the lamin A/C gene, which leads to substitution of an amino acid at position 347 of the protein (p.Glu347Lys) and is a known cause of DCM.</p><p id="par0080" class="elsevierStylePara elsevierViewall">It was decided to perform electrophysiological study (EPS) for stratification of arrhythmic risk, which showed an atrial-His interval of 186 ms, His-ventricle interval of 60 ms, and an antegrade Wenckebach point of 635 ms. Sinus node recovery time was normal. Right ventricular pacing in the apex and outflow tract with 600- and 400-ms drive cycle lengths and up to three extrastimuli at intervals of at least 200 ms did not trigger sustained ventricular arrhythmias.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Given the failure to induce ventricular arrhythmias during EPS and the patient's refusal to have an implantable cardioverter-defibrillator (ICD), it was decided to maintain clinical follow-up and six-monthly echocardiograms and to implant an event loop recorder with remote monitoring.</p><p id="par0090" class="elsevierStylePara elsevierViewall">The results of genetic testing of the patient's first-degree relatives are awaited.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0095" class="elsevierStylePara elsevierViewall">No specific feature has so far been identified that distinguishes cardiomyopathy associated with <span class="elsevierStyleItalic">LMNA</span> mutations from other forms of idiopathic DCM. It is characterized by dilatation and systolic dysfunction of one or both ventricles, myocyte destruction and myocardial fibrosis,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">9</span></a> and it is thus necessary to investigate more common etiologies of DCM.</p><p id="par0100" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">LMNA</span> mutations are found in 6% of all cases of DCM,<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10,11</span></a> in 7.5% of familial forms and in 3.6–11% of sporadic forms.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a> They have also been identified in 33% of DCM patients with conduction system disease<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">13</span></a>; the prevalence of variants of uncertain significance in the general healthy population is estimated at 4%.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">In Portugal, the incidence of this etiology in patients with non-ischemic DCM is currently being assessed in the FATIMA study, mutations in the <span class="elsevierStyleItalic">LMNA</span> gene being investigated in all the subjects included.<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">15</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">While the pattern of transmission is generally autosomal dominant, cases have been reported of an autosomal recessive pattern and of sporadic mutations. Penetrance is virtually 100% in carriers by the age of 60, with phenotypic expression of varying severity.<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">16</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The conduction system can be affected at practically all levels, and disturbances typically occur before ventricular dilatation.</p><p id="par0120" class="elsevierStylePara elsevierViewall">Of the more than 30 genes in which mutations have been identified as causing DCM, only two are also associated with conduction disturbances: <span class="elsevierStyleItalic">LMNA</span> and <span class="elsevierStyleItalic">SCN5A</span>.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">12,17</span></a> Thus, the presence of DCM and conduction disorders should arouse a high level of suspicion, and an even higher level when there is also evidence of skeletal muscle abnormalities. Genetic testing for <span class="elsevierStyleItalic">LMNA</span> and <span class="elsevierStyleItalic">SCN5A</span> mutations in the presence of DCM of undetermined etiology and first-degree or higher AVB is a class I recommendation in the recent HRS/EHRA expert consensus statement.<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Tachyarrhythmias can also occur in the early phase of the disease, before and independently of the development of ventricular dilatation, sudden death being the first manifestation in some cases. In a study by van Berlo et al.,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a> 46% of mortality was due to sudden death, compared to 12% due to pump failure. Furthermore, 43% of the victims of sudden death had pacemakers for conduction system disease.</p><p id="par0130" class="elsevierStylePara elsevierViewall">In a recent reference study,<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">19</span></a> the incidence of sudden death, fatal or aborted after cardiopulmonary resuscitation or ICD shock, was 18% in a mean follow-up of 43 months. Mean age at death was 50±11 years. Independent predictors of sudden death were ejection fraction <45% at the beginning of follow-up, documented non-sustained VT and male gender. No patient with none of these risk factors suffered malignant ventricular arrhythmias, while these occurred in 1.7%, 27% and 54% of those with one, two or three risk factors, respectively. A recent study of 41 patients concluded that the best predictor of arrhythmic risk was the presence of first-degree AVB.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">20</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The natural history of DCM due to <span class="elsevierStyleItalic">LMNA</span> mutations is aggressive. One epidemiological study estimated that 55% of carriers die from cardiovascular cause or are referred for transplantation by the age of 60, compared to only 11% of idiopathic DCM patients without mutations.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">12</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Characteristically, arrhythmic manifestations begin in the third decade of life (over 90% of patients present at this age).<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a> Conduction disturbances warrant pacemaker implantation in 44% of patients, although this does not necessarily protect them from sudden death.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a> In typical cases, signs of heart failure become apparent 15–20 years after the appearance of arrhythmias.</p><p id="par0145" class="elsevierStylePara elsevierViewall">At present there is no specific treatment for cardiolaminopathies. However, the observation that the enzymes ERK 1/2 and JNK are overexpressed in carriers of LMNA mutations<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">21</span></a> has opened up a line of research into the effect of pharmacological blockade of these pathways in mouse models,<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">22</span></a> but this has yet to be tested in humans.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Drug therapy is in accordance with state-of-the-art treatment for other forms of DCM, but it is not clear whether use of the standard drugs to slow disease progression is warranted in silent carriers.</p><p id="par0155" class="elsevierStylePara elsevierViewall">ICD implantation should be considered when arrhythmia or ventricular dilatation is documented in patients with mutations, especially when two or more of the above risk factors are present. This approach is of course not based on prospective clinical trials as it is a recently described rare disease, and thus has a level of evidence C. The incidence of sudden death in patients with pacemakers is such that some authors recommend ICD implantation for primary prevention in pacemaker candidates.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">23</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">There is as yet no evidence to support prophylactic ICD implantation in asymptomatic carriers. The role of EPS in stratifying risk for tachycardia and bradycardia has also yet to be established.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Some known risk factors were present in the case presented, including male gender, non-sustained VT on Holter monitoring, first-degree AVB and ventricular dilatation. Nevertheless, given the lack of indications for ICD implantation or pacemaker with a level of evidence A or B (no higher than first-degree and predominantly supra-Hisian AVB and asymptomatic) and the failure to induce ventricular arrhythmias on EPS (of uncertain significance), together with the patient's refusal of this option, it was decided to implant an event loop recorder for remote continuous heart rhythm monitoring to detect conduction blocks or ventricular arrhythmias, even if asymptomatic.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conclusion</span><p id="par0170" class="elsevierStylePara elsevierViewall">Mutations in the lamin A/C genes result in the phenotype of various diseases, most related to the musculoskeletal system. Cardiac involvement can be manifested by dilatation and systolic dysfunction, ventricular arrhythmias and conduction disturbances. Male gender, non-sustained VT on Holter monitoring, increased PR interval and ejection fraction <45% are the risk factors for sudden death so far described in small series. The role of EPS in stratifying arrhythmic risk has yet to be established.</p><p id="par0175" class="elsevierStylePara elsevierViewall">A high index of suspicion and referral for genetic testing are essential to improve the prognosis of affected patients given the particularly aggressive course of the disease compared to most other forms of DCM.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ethical disclosures</span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Protection of human and animal subjects</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Confidentiality of data</span><p id="par0185" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Right to privacy and informed consent</span><p id="par0190" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conflicts of interest</span><p id="par0195" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres439409" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims and Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Case report" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Discussion" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec462598" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres439410" "titulo" => "Resumo" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos e métodos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Caso clínico" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Discussão" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusão" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec462599" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conclusion" ] 8 => array:3 [ "identificador" => "sec0025" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0030" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0035" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0040" "titulo" => "Right to privacy and informed consent" ] ] ] 9 => array:2 [ "identificador" => "sec0045" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-06-02" "fechaAceptado" => "2014-08-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec462598" "palabras" => array:3 [ 0 => "Laminopathy" 1 => "<span class="elsevierStyleItalic">LMNA</span> gene mutations" 2 => "Dilated cardiomyopathy" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec462599" "palabras" => array:3 [ 0 => "Laminopatia" 1 => "Mutações no gene LMNA" 2 => "Miocardiopatia dilatada" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The <span class="elsevierStyleItalic">LMNA</span> gene encodes a group of proteins that have an important structural and functional role in the cell nucleus. Mutations in this gene have been found in 6% of all forms of dilated cardiomyopathy and in up to 33% of those with conduction system disturbances.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Aims and Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Using a case report as an example, we performed a review of the literature on the pathophysiological mechanisms, clinical manifestations, risk stratification and treatment options of cardiac involvement in laminopathies.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case report</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We present the case of a 46-year-old man, whose ECG showed bizarre voltage criteria for left ventricular hypertrophy and first-degree atrioventricular block, a dilated left ventricle with mildly impaired global systolic function and non-sustained ventricular tachycardia on Holter monitoring, and with a family history of sudden death. Genetic testing identified an <span class="elsevierStyleItalic">LMNA</span> mutation. No ventricular arrhythmias were induced during electrophysiological study. The patient is under close clinical and echocardiographic monitoring and an event loop recorder has been implanted.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Phenotypically, myocardial involvement in laminopathies is indistinguishable from other forms of idiopathic dilated cardiomyopathy. Ventricular arrhythmias are common, but the best method for sudden death risk stratification has yet to be established. The few studies that have been performed, with a very limited number of patients, show that factors associated with an unfavorable prognosis are ejection fraction <45%, non-sustained ventricular tachycardia, male gender and any form of atrioventricular block. Given the lack of evidence, indications for an implantable cardioverter-defibrillator for primary prevention in this context are the same as conventional indications for other forms of idiopathic dilated cardiomyopathy.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Cardiac involvement as a consequence of <span class="elsevierStyleItalic">LMNA</span> mutations generally has a more aggressive natural history than other forms of non-ischemic dilated cardiomyopathy. A high index of suspicion and prompt referral for genetic testing are essential for appropriate therapeutic management.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aims and Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Case report" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Discussion" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "pt" => array:3 [ "titulo" => "Resumo" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introdução</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">O gene LMNA codifica proteínas que têm um papel estrutural e funcional importante a nível do núcleo celular. As suas mutações foram encontradas em 6% de todas as formas de miocardiopatia dilatada (MCD) e em 33% das formas que cursam com perturbações no sistema de condução.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos e métodos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Partindo da descrição de um caso clínico, é feita uma revisão da evidência existente acerca dos mecanismos fisiopatológicos, manifestações, estratificação de risco e tratamento das laminopatias com atingimento cardíaco.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Caso clínico</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">É apresentado o caso clínico de um homem de 46 anos com critérios de voltagem bizarros para hipertrofia ventricular esquerda no ECG, dilatação e ligeira depressão da função sistólica ventricular esquerda e bloqueio auriculoventricular de 1.° grau, arritmias ventriculares não mantidas polimórficas em Holter e história de morte súbita familiar. O teste genético foi positivo para mutação no gene LMNA. Foi submetido a estudo eletrofisiológico no qual não se induziram arritmias ventriculares. O doente foi mantido sob vigilância clínica e ecocardiográfica e implantado detetor de eventos.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Discussão</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Fenotipicamente, o atingimento miocárdico é indistinguível do das outras formas de MCD idiopática. As arritmias ventriculares são frequentes e a forma de melhor estratificar o risco de morte súbita está ainda por definir. Estão disponíveis resultados de poucos estudos e com um número muito limitado de doentes, sendo que os fatores de mau prognóstico identificados por estes foram: fração de ejeção < 45%, TV não mantidas, sexo masculino e presença de qualquer forma de bloqueio auriculoventricular. Dada a fraca evidência disponível, as indicações formais para implantação de CDI em prevenção primária neste contexto não são ainda diferentes das indicações convencionais noutras formas de MCD idiopática.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusão</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">O atingimento cardíaco como consequência da mutação no gene LMNA apresenta uma história natural geralmente mais agressiva do que a maior parte das demais formas de MCD não isquémica. Um índice de suspeição elevado e o pedido atempado do teste genético são essenciais para a estratégia terapêutica.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introdução" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos e métodos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Caso clínico" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Discussão" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusão" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Cabanelas N, Martins VP. Laminopatias: uma caixa de Pandora com insuficiência cardíaca, bradiarritmias e morte súbita. Rev Port Cardiol. 2015;34:139.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Striated muscle disease</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Emery-Dreifuss muscular dystrophy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Congenital muscular dystrophy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Limb-girdle muscular dystrophy type 1B \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dilated cardiomyopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Lipodystrophy</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Dunnigan lipodystrophy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lipoatrophy with diabetes and insulin resistance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Lipoatrophy without insulin resistance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mandibuloacral dysplasia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Peripheral neuropathy</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Charcot-Marie-Tooth disease type 2B1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleItalic">Premature aging disease (progerias)</span> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Werner syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Hutchinson-Gilford syndrome \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Restrictive dermopathy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Progeroid variant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Mandibuloacral dysplasia \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab685925.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Laminopathies.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:23 [ 0 => array:3 [ "identificador" => "bib0120" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F. 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Worman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/ncb1104-1062" "Revista" => array:6 [ "tituloSerie" => "Nat Cell Biol" "fecha" => "2004" "volumen" => "6" "paginaInicial" => "1062" "paginaFinal" => "1067" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15517000" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0130" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "T. Dechat" 1 => "K. Pfleghaar" 2 => "K. Sengupta" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1101/gad.1652708" "Revista" => array:6 [ "tituloSerie" => "Genes Dev" "fecha" => "2008" "volumen" => "22" "paginaInicial" => "832" "paginaFinal" => "853" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18381888" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0135" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "LMNA mutation position predicts organ system involvement in laminopathies" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 10 | 6 | 16 |
| 2024 October | 72 | 37 | 109 |
| 2024 September | 89 | 27 | 116 |
| 2024 August | 66 | 28 | 94 |
| 2024 July | 41 | 25 | 66 |
| 2024 June | 46 | 23 | 69 |
| 2024 May | 61 | 26 | 87 |
| 2024 April | 50 | 25 | 75 |
| 2024 March | 41 | 21 | 62 |
| 2024 February | 48 | 21 | 69 |
| 2024 January | 48 | 27 | 75 |
| 2023 December | 43 | 24 | 67 |
| 2023 November | 57 | 26 | 83 |
| 2023 October | 32 | 14 | 46 |
| 2023 September | 45 | 20 | 65 |
| 2023 August | 47 | 15 | 62 |
| 2023 July | 46 | 16 | 62 |
| 2023 June | 49 | 21 | 70 |
| 2023 May | 57 | 24 | 81 |
| 2023 April | 41 | 4 | 45 |
| 2023 March | 84 | 30 | 114 |
| 2023 February | 63 | 24 | 87 |
| 2023 January | 39 | 5 | 44 |
| 2022 December | 83 | 24 | 107 |
| 2022 November | 90 | 28 | 118 |
| 2022 October | 55 | 23 | 78 |
| 2022 September | 68 | 42 | 110 |
| 2022 August | 92 | 35 | 127 |
| 2022 July | 53 | 44 | 97 |
| 2022 June | 52 | 34 | 86 |
| 2022 May | 54 | 38 | 92 |
| 2022 April | 60 | 30 | 90 |
| 2022 March | 72 | 50 | 122 |
| 2022 February | 52 | 24 | 76 |
| 2022 January | 56 | 28 | 84 |
| 2021 December | 45 | 34 | 79 |
| 2021 November | 53 | 29 | 82 |
| 2021 October | 48 | 35 | 83 |
| 2021 September | 35 | 28 | 63 |
| 2021 August | 61 | 35 | 96 |
| 2021 July | 28 | 23 | 51 |
| 2021 June | 49 | 23 | 72 |
| 2021 May | 59 | 28 | 87 |
| 2021 April | 132 | 33 | 165 |
| 2021 March | 87 | 19 | 106 |
| 2021 February | 117 | 20 | 137 |
| 2021 January | 69 | 17 | 86 |
| 2020 December | 75 | 13 | 88 |
| 2020 November | 48 | 15 | 63 |
| 2020 October | 55 | 11 | 66 |
| 2020 September | 74 | 8 | 82 |
| 2020 August | 22 | 3 | 25 |
| 2020 July | 68 | 9 | 77 |
| 2020 June | 52 | 8 | 60 |
| 2020 May | 47 | 11 | 58 |
| 2020 April | 53 | 22 | 75 |
| 2020 March | 54 | 7 | 61 |
| 2020 February | 87 | 19 | 106 |
| 2020 January | 39 | 5 | 44 |
| 2019 December | 37 | 6 | 43 |
| 2019 November | 53 | 13 | 66 |
| 2019 October | 41 | 8 | 49 |
| 2019 September | 22 | 9 | 31 |
| 2019 August | 38 | 8 | 46 |
| 2019 July | 60 | 16 | 76 |
| 2019 June | 32 | 5 | 37 |
| 2019 May | 37 | 10 | 47 |
| 2019 April | 34 | 16 | 50 |
| 2019 March | 83 | 12 | 95 |
| 2019 February | 73 | 12 | 85 |
| 2019 January | 58 | 5 | 63 |
| 2018 December | 70 | 10 | 80 |
| 2018 November | 97 | 13 | 110 |
| 2018 October | 153 | 15 | 168 |
| 2018 September | 46 | 11 | 57 |
| 2018 August | 79 | 11 | 90 |
| 2018 July | 37 | 5 | 42 |
| 2018 June | 45 | 13 | 58 |
| 2018 May | 52 | 10 | 62 |
| 2018 April | 37 | 7 | 44 |
| 2018 March | 53 | 18 | 71 |
| 2018 February | 31 | 8 | 39 |
| 2018 January | 34 | 10 | 44 |
| 2017 December | 68 | 11 | 79 |
| 2017 November | 59 | 21 | 80 |
| 2017 October | 49 | 16 | 65 |
| 2017 September | 66 | 26 | 92 |
| 2017 August | 59 | 20 | 79 |
| 2017 July | 46 | 16 | 62 |
| 2017 June | 59 | 14 | 73 |
| 2017 May | 74 | 25 | 99 |
| 2017 April | 49 | 16 | 65 |
| 2017 March | 57 | 22 | 79 |
| 2017 February | 63 | 8 | 71 |
| 2017 January | 53 | 14 | 67 |
| 2016 December | 62 | 9 | 71 |
| 2016 November | 47 | 9 | 56 |
| 2016 October | 56 | 15 | 71 |
| 2016 September | 43 | 10 | 53 |
| 2016 August | 14 | 5 | 19 |
| 2016 July | 24 | 13 | 37 |
| 2016 June | 9 | 13 | 22 |
| 2016 May | 23 | 13 | 36 |
| 2016 April | 53 | 2 | 55 |
| 2016 March | 73 | 26 | 99 |
| 2016 February | 96 | 34 | 130 |
| 2016 January | 55 | 22 | 77 |
| 2015 December | 60 | 18 | 78 |
| 2015 November | 81 | 29 | 110 |
| 2015 October | 63 | 32 | 95 |
| 2015 September | 58 | 34 | 92 |
| 2015 August | 48 | 20 | 68 |
| 2015 July | 40 | 28 | 68 |
| 2015 June | 34 | 19 | 53 |
| 2015 May | 44 | 31 | 75 |
| 2015 April | 61 | 26 | 87 |
| 2015 March | 110 | 77 | 187 |
| 2015 February | 10 | 5 | 15 |
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